Unlocking Cagrilintide Benefits for Obesity: A Research Review

Introduction

Obesity and type 2 diabetes mellitus pose urgent global health challenges, driving a search for new pharmacotherapies that can bridge the gap between lifestyle changes and invasive measures like bariatric surgery. Recently, Cagrilintide – a novel long-acting analogue of the hormone amylin – has emerged as a promising candidate in this space.  

 

Cagrilintide is designed to mimic and enhance the effects of native amylin, a neuroendocrine peptide co-secreted with insulin that helps regulate appetite and postprandial glucose. By activating amylin receptors in the brain, this analogue induces satiety (feelings of fullness), slows gastric emptying, and suppresses inappropriate glucagon secretion. Uniquely, cagrilintide is being developed in combination with glucagon-like peptide-1 (GLP-1) receptor agonists (notably semaglutide) to achieve synergistic weight loss and metabolic controlpubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov. This combined approach (termed “CagriSema” when cagrilintide is paired with semaglutide) targets multiple complementary pathways of appetite regulation, reflecting a broader strategy of using multi-hormone therapy to treat obesity’s complex pathophysiology. Early clinical studies suggest that cagrilintide – both alone and alongside GLP-1 analogues – can produce substantial, sustained weight loss while improving glycaemic control.  

 

In this article, we provide a comprehensive overview of cagrilintide, including its chemical profile, mechanism of action, preclinical research, clinical trial results in obesity and diabetes, pharmacokinetics, safety, and current status in drug development.  

 

Chemical Profile of Cagrilintide

Cagrilintide is a synthetic peptide analogue of human amylin engineered for much longer duration of action. Chemically, it is a peptide of 37 amino acids (like native amylin) with strategic modifications to enhance stability and half-life. Notably, cagrilintide is lipidated – a fatty acid chain is attached to the peptide – which enables reversible binding to albumin and shields it from rapid degradationpubs.acs.org. This design significantly prolongs its circulation time compared to the short-lived natural hormone.  

 

Key chemical identifiers of cagrilintide are given below:

• IUPAC name: 20-[[(1S)-4-[[(2S)-6-amino-1-[[(4R,7S,10S,13S,16S,19R)-4-[[(2S)-1- [[(2S,3R)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1- [[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2R)-4-amino-1-[[(2S)-1-[[2-[(2S)-2-[[(2S,3S)- 1- [[(2S)-1-[(2S)-2-[(2S)-2-[[(2S,3R)-1-[[(2S)-4-amino-1-[[(2S,3R)-1-[(2S)-2- carbamoylpyrrolidin-1-yl]-3-hydroxy-1-oxobutan-2-yl]amino]-1,4-dioxobutan-2- yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1- oxobutan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2- yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2- oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]- 1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1- oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5- carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]- 1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1- oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido- 1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2- yl]amino]-1-oxopropan-2-yl]carbamoyl]-16-(2-amino-2-oxoethyl)-7,13-bis[(1R)-1- hydroxyethyl]-10-methyl-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentazacycloicos-19-yl]amino]-1-oxohexan-2-yl]amino]-1-carboxy-4- oxobutyl]amino]-20-oxoicosanoic acid (this expansive name reflects the full amino acid sequence with lipidation).  
• CAS Number: 1415456-99-3  
• Molecular formula: C_194H_312N_54O_59S_2 (corresponding to a molecular weight of approximately 4409 g/mol)  
• PubChem CID: 167312356 (compound entry providing structure and physicochemical data)  

These identifiers highlight cagrilintide’s nature as a large, peptide-based drug. Its amino acid sequence is derived from human islet amyloid polypeptide (amylin) but includes substitutions (such as proline residues in positions prone to aggregation) to prevent the peptide from forming amyloid fibrils. Indeed, similar substitutions were used in the older amylin analogue pramlintide to improve stability and solubility. In addition, cagrilintide’s N-terminus is modified with a fatty diacid moiety via a linker, a strategy inspired by other peptide therapeutics (like acylated insulin analogues and GLP-1 analogues such as semaglutide) to extend its duration of action. The result is a stable amylin agonist that can be administered once weekly rather than before each meal. By virtue of its molecular design, cagrilintide resists rapid enzymatic degradation and clearance, allowing it to circulate long enough to exert sustained pharmacological effects over days.  

 

Mechanism of Action

Cagrilintide’s pharmacology is rooted in that of amylin, a hormone that complements insulin’s actions. Amylin exerts its effects by binding to amylin receptors, which are heterodimeric G-protein-coupled receptors formed by the calcitonin receptor (CTR) coupled with one of three receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3). These combinations (AMY_1, AMY_2, and AMY_3 receptor subtypes) are abundantly expressed in key regions of the brain that regulate appetite and glucose metabolism – particularly the area postrema and nucleus of the solitary tract in the brainstem, as well as hypothalamic nuclei involved in satiety. Activation of amylin receptors triggers signalling pathways that promote satiety and reduce food intake, partly by enhancing feelings of fullness and reducing hedonic eating drive. Additionally, amylin slows the rate at which food empties from the stomach into the intestine (gastric emptying), thereby blunting postprandial glucose spikes, and it suppresses the inappropriate release of glucagon after meals. These actions make amylin an appealing target for both weight management and glycaemic control. Pramlintide, a short-acting amylin analog, has been used in diabetes treatment to smooth post-meal glucose excursions, albeit with modest weight loss.  

 

Cagrilintide, as a long-acting amylin analogue, binds to the same receptors with high affinity and full agonist activity, but remains active in the circulation for a much longer duration. It effectively amplifies the physiological roles of amylin by continuously engaging amylin receptors throughout the week. The net result is a persistent reduction in caloric intake and a sustained dampening of postprandial glucose fluctuations. Importantly, because cagrilintide is administered subcutaneously once weekly, it maintains relatively steady plasma levels, avoiding the peaks and troughs associated with pramlintide injections and thus providing a more consistent anorectic (appetite-suppressing) effect.  

 

One of the most exciting aspects of cagrilintide is how it synergises with GLP-1 receptor agonists. GLP-1 receptor agonists (such as semaglutide) act on a different hormone system: they activate GLP-1 receptors in the pancreas (to enhance glucose-dependent insulin secretion and suppress glucagon) and in the brain (notably the hypothalamus) to reduce appetite and food intake. Like amylin, GLP-1 agonists also delay gastric emptying (although this effect may attenuate over time with chronic use). Cagrilintide and GLP-1 analogues have distinct but complementary mechanisms, engaging separate receptors and neural pathways that both lead to eating less and feeling fullpubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov. Amylin primarily influences the brainstem satiety center and mesolimbic reward pathways (thereby affecting both homeostatic and hedonic feeding), whereas GLP-1 acts strongly on hypothalamic circuits that regulate appetite and energy balance. When used together, these agents produce an additive (and possibly synergistic) effect on weight reduction, greater than either alone. In essence, CagriSema (cagrilintide + semaglutide) tackles obesity through a dual-hormone approach: one component (semaglutide) powerfully reduces hunger and improves insulin/glucagon balance via GLP-1 receptors, while the other (cagrilintide) reinforces fullness and further curbs appetite via amylin receptorspubmed.ncbi.nlm.nih.gov. This dual agonism leads to enhanced satiety signals, significant caloric intake reduction, and thus pronounced weight loss. Notably, preclinical studies in animal models first demonstrated this synergy – co-administration of an amylin analog with a GLP-1 analog produced far greater weight loss than either agent alone – paving the way for trials of the combination in humans. Given the complex, multi-factorial nature of obesity, such combination therapy targeting multiple hormonal pathways is viewed as a logical strategy to achieve greater efficacy than single-agent treatment.  

 

At the cellular level, structural biology research has begun to elucidate how cagrilintide interacts with its receptor. Recent high-resolution studies resolved the structure of cagrilintide bound to the active amylin receptor (CTR–RAMP complexes), showing the peptide engaging the receptor in a manner that stabilises the active G protein-coupled conformationnature.com. The lipidated tail of cagrilintide appears to associate with the receptor or membrane in a way that may prolong receptor binding or assist in receptor activation. These insights help explain cagrilintide’s potent agonism and long duration of action at the amylin receptor, as well as guide future peptide drug designs. In summary, by mimicking amylin’s actions over an extended period, cagrilintide powerfully suppresses appetite and modulates digestion, and when combined with GLP-1 analogues, it engages complementary pathways to produce unprecedented levels of weight loss in clinical studies.  

 

Preclinical Research

Before cagrilintide ever entered human trials, extensive preclinical research was conducted to characterise its pharmacology, efficacy in animal models, and safety profile. In vitro studies confirmed that cagrilintide is a high-affinity agonist at human amylin receptors. The peptide was shown to stimulate the amylin receptor signal transduction (e.g. cAMP generation in cell assays) as effectively as native amylin, indicating it is a full agonist. Compared to human amylin, cagrilintide’s modified sequence greatly improved its stability: it resists aggregation into amyloid fibrils and is less susceptible to enzymatic proteolysis. This means that in laboratory conditions and likely in circulation, cagrilintide remains intact and bioactive far longer than the natural hormone. Its lipid conjugation also did not impair receptor activation; rather, it provided a novel way to enhance pharmacokinetics without sacrificing potency. Receptor-binding studies have suggested that cagrilintide may have slightly altered receptor subtype selectivity compared to amylin – for instance, it can activate all amylin receptor subtypes and also has some activity at the calcitonin receptor alone (CTR without a RAMP). This broad activity is typical of amylin analogues and may contribute to its physiological effects (since CTRs and amylin receptors overlap in distribution).  

 

In animal models, cagrilintide demonstrated powerful anorectic and weight-loss effects consistent with its mechanism. Rodent studies, including diet-induced obese rats or genetically obese mice, showed that cagrilintide dose-dependently reduced food intake and body weight. When administered to rodents, the compound caused a sustained decrease in daily food consumption and gradual weight loss over time, without causing hypoglycaemia (since amylin’s actions are insulin-dependent and do not override normal glucose regulation). Importantly, combination experiments in animals provided early evidence of synergy: animals treated with both a GLP-1 analogue (such as ecnoglutide, an experimental GLP-1 RA) and an amylin analogue lost markedly more weight than those treated with either agent alone, far exceeding additive expectationsbiospace.combiospace.com. These findings mirrored earlier observations that even in humans, pramlintide (amylin analog) combined with metreleptin (leptin analog) or with phentermine yielded greater weight loss than monotherapy – reinforcing the concept that multi-hormonal interventions can unlock more weight reduction by addressing multiple appetite pathways. Cagrilintide’s robust preclinical efficacy and tolerability in animals supported its advancement into human trials.  

 

Safety pharmacology studies in animals indicated that cagrilintide did not have concerning off-target effects at therapeutic doses. There were no significant adverse cardiovascular effects (e.g. no signal of heart valve damage or tachycardia beyond what is expected from weight loss). The main observed effects were those related to its mode of action: reduced food intake and slower gastric motility. In toxicology studies, very high doses caused exaggerated pharmacological effects (such as marked weight loss and decreased nutritional intake in animals), but no organ toxicity or unexpected pathology. These results suggested a wide safety margin. Cagrilintide, like native amylin and pramlintide, does not cross the blood–brain barrier in large amounts; instead, it likely acts on accessible receptors in the circumventricular organs (like area postrema) to influence brain circuits. This means it is not expected to have direct central nervous system toxicity. Additionally, because its amino acid sequence is human-based, the risk of immunogenicity (anti-drug antibody formation) is anticipated to be low – though this would be monitored in clinical trials.  

 

In summary, preclinical research established cagrilintide as a potent, long-acting amylin mimetic that safely produces weight loss in animal models. These studies provided the rationale for testing cagrilintide in humans, both as a single agent and in combination with GLP-1 analogues, to harness the enhanced weight-lowering effect observed in animals. By the time of first-in-human testing, cagrilintide had demonstrated a favourable profile: strong efficacy in reducing food intake and weight, a benign safety/toxicology record, and a unique pharmacokinetic design suited for weekly dosing.  

 

Clinical Trials and Efficacy

Phase 1: First-in-Human and Combination Feasibility

Initial human studies of cagrilintide focused on assessing its safety, tolerability, pharmacokinetics (PK), and pharmacodynamic effects. A Phase 1 trial in healthy volunteers and individuals with overweight evaluated single and multiple ascending doses of cagrilintide given by subcutaneous injection. These early trials confirmed the peptide’s prolonged half-life and dose-dependent pharmacology in humans.  

 

Notably, a multiple-dose Phase 1b trial investigated cagrilintide administered alongside semaglutide 2.4 mg (the standard anti-obesity dose of semaglutide) to ensure the combination could be used safelypubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov. In this 19-week study, participants without diabetes and with BMI 27–40 received various doses of weekly cagrilintide (ranging from 0.16 mg up to 4.5 mg) or placebo, co-escalated with semaglutide up to 2.4 mg weeklypubmed.ncbi.nlm.nih.gov. The results were encouraging: cagrilintide was well tolerated both alone and in combination with semaglutide, with an adverse event profile largely limited to mild gastrointestinal symptoms (a pattern similar to that of GLP-1 agonists alone). There were no serious safety concerns or unexpected effects from the combined administration. Importantly, the pharmacokinetic profiles of both drugs were virtually unchanged by co-administration – cagrilintide’s absorption and clearance were not affected by semaglutide, and vice versa, indicating no significant drug–drug interaction. Cagrilintide’s half-life in humans was measured at roughly 159–195 hours (approximately 6.6–8.1 days)pubmed.ncbi.nlm.nih.gov, supporting once-weekly dosing. Peak plasma concentrations of cagrilintide were typically reached between 24–72 hours after injection, reflecting slow absorption kinetics consistent with its acylated designpubmed.ncbi.nlm.nih.gov. These Phase 1 findings confirmed the translational potential of cagrilintide: a single weekly injection could achieve steady therapeutic levels, and combining it with semaglutide did not compromise safety or efficacy. Additionally, although Phase 1 studies were not primarily efficacy trials, they did record early signs of weight loss and reduced appetite in participants receiving the higher doses of cagrilintide (especially in combination with semaglutide), hinting at the powerful effect to be quantified in subsequent trials.  

 

Phase 2: Dose-Finding in Obesity and Proof-of-Concept in Type 2 Diabetes

After establishing safety in Phase 1, researchers moved to Phase 2 trials to evaluate cagrilintide’s efficacy for weight management and to determine optimal dosing. One major Phase 2 study was a dose-finding trial in people with obesity, published in The Lancet in late 2021pubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. In this multicentre trial (often referred to as the “STEP AMY” trial, in line with the semaglutide obesity trials naming convention), 706 adults without diabetes and with BMI in the obese range were randomised to receive one of five doses of cagrilintide (0.3, 0.6, 1.2, 2.4, or 4.5 mg weekly), or an active comparator of liraglutide 3.0 mg daily (the then-standard GLP-1 obesity therapy), or placebopubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov. Treatment lasted 26 weeks, with a dose-escalation period in the cagrilintide groups to mitigate side effects. All participants also received lifestyle counseling for diet and exercise. The primary endpoint was percent change in body weight from baseline at 26 weeks.  

 

The Phase 2 results were impressive: all doses of cagrilintide produced significantly greater weight loss than placebopubmed.ncbi.nlm.nih.gov. ¹ Weight reduction was dose-dependent, ranging from about -6.0% at the 0.3 mg dose to -10.8% at the highest 4.5 mg dose (an average loss of ~11.5 kg) over 26 weekspubmed.ncbi.nlm.nih.gov. ¹ By contrast, the placebo group lost only about 3.0% (~3.3 kg).